Other evidence shows that alcohol exposure elicits functional and structural plasticity selectively in D1-MSNs. Further, D1-like antagonists impair alcohol-seeking in an operant task. Pharmacological blockade of D1-like receptors, but not D2-like receptors, attenuates alcohol consumption when delivered in the dorsomedial striatum. Deletion of the gene encoding for D1R ( Drd1a) impairs alcohol drinking and preference. In the striatum, D1R are expressed in the direct pathway medium spiny neurons (D1- MSNs) and regulate the reinforcing properties of alcohol. Thus, LRRK2 is proposed to limit D1R signaling via PKA pathway in the direct-pathway medium spiny neurons of the striatum. Gain-of-function mutations of Lrrk2 were shown to reduce PKA activity. Global deletion of Lrrk2 enhanced protein kinase A signaling downstream of D1R and altered dendritic spine morphology and synaptic strength in striatal medium spiny neurons of developing mice. Mutations in Lrrk2 alter membrane trafficking and surface expression of D1R. LRRK2 was shown to act as a negative modulator of dopamine D1 receptors (D1R) within the striatum. However, it remains unclear whether this association is causal, and which are possible mechanisms underlying the impact of LRRK2 activity on alcohol reinforcement. A positive correlation between striatal levels of Lrrk2 mRNA and alcohol drinking was reported in mice, especially an association with inflexible alcohol drinking that persists despite adverse outcomes or punishment. Recent work has linked changes in striatal expression of the Lrrk2 gene with alcohol drinking in humans and rodents. Mutations in the human LRRK2 gene are associated with Parkinson’s disease, which is characterized by prominent impairment in dopamine signaling and basal ganglia function. The leucine-rich repeat kinase 2 ( Lrrk2) gene is highly expressed in the striatum and plays an important role in regulating synapse formation and synaptic transmission. In fact, functional and morphological alterations in the striatal circuitry have been linked to AUD and we hypothesize that difference in the striatal circuitry can drive vulnerability for developing AUD. The striatum plays a central role in learning and execution of reward-motivated behaviors, making this brain region very relevant for substance use disorders. Only a fraction (~8%) of those who consume alcohol are diagnosed with AUD each year, pointing to the existence of risk and resilience factors for developing the disorder. Loss of control over alcohol drinking leads to abuse and hinders long-term abstinence, driving relapse. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.Īlcohol use disorder (AUD) is a chronic relapsing disorder characterized by an inability to stop alcohol use despite adverse consequences. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Here, we report that the Parkinson’s-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers.
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